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Synthesis 2009(15): 2509-2516  
DOI: 10.1055/s-0029-1216885
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Pyrrolidine-Based Organocatalysts for Enantioselective Michael Addition of Cyclohexanone to trans-β-Nitrostyrene

Allison P. Carley, Sally Dixon, Jeremy D. Kilburn*
School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK
Fax: +44(23)80594182; e-Mail: jdk1@soton.ac.uk;
Further Information

Publication History

Received 11 March 2009
Publication Date:
07 July 2009 (online)

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Abstract

A series of readily prepared bifunctional catalysts promote the Michael addition of cyclohexanone to trans-β-nitrostyrene with excellent asymmetric induction. The enantioselection (up to 97%) and diastereoselection (up to 95:5) is comparable to other pyrrolidine­-thiourea organocatalysts recently reported, however, reaction times are often shorter.

Key words

addition reactions - asymmetric catalysis - Michael additions­ - bifunctional catalysis - nitroolefin

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14

We also prepared pyrrolidines with 2-carboxamide- or 2-methylacetamide-tethered thiourea and thiouronium functionality. Attempted catalysis of the conjugate addition of cyclohexanone to trans-β-nitrostyrene typically resulted in a syn/anti diastereomeric product ratio of >91:9 with carboxamide-tethered catalysts, comparable to that seen with monofunctional catalysis by (2S)-N-benzylpyrrolidine-2-carboxamide. However, poor syn enantioselectivity (<30% ee) resulted and all methylacetamide-tethered examples demonstrated little or no catalytic activity. Similar amide-linked, amine-thiourea catalysts were also reported to give only the racemic product of ketone addition to nitro-olefins during the course of our study (ref. 7e), presumably as a result of intramolecular hydrogen bonding between thiourea/uronium functionality and the tethering amide.

18

To our knowledge, comparable rates of catalysis for the Michael addition of ketones to nitroalkenes only by diamines have been reported; see references 4e, 6a, and 6b.

20

A 3:1 ratio of syn/anti with catalyst 13 was the best result obtained. The reaction was conducted with 0.5 mmol trans-β-nitrostyrene in 0.75 mL toluene, 15 mol% 13, 0.15 equiv AcOH and 1 equiv H2O at r.t. Typically syn/anti diastereo-meric ratios of 1:1 or 2:1 resulted with catalysts 4, 6, 7, 10, 12, or 14; major diastereoisomer ee (%) ranged between 8-77%.

21

Configuration of (S)-2-[(R)-2-nitro-1-phenylethyl]cyclo-hexanone (16) was determined by literature comparison of HPLC elution order, see ref. 7e; and optical rotation; [α]D -26.7 (c = 1.0, CHCl3, 24 ˚C), see ref. 22.